Cardiovascular disease is the leading cause of death among Americans. Among those who survive an initial cardiovascular event such as a myocardial infarction or heart attack there is a high level of morbidity resulting from ischemia. As used in the specification and in the claims "ischemia" is defined as a decrease in the blood supply to a bodily organ or tissue caused by constriction or obstruction of the blood vessels. During the acute stage of a heart attack the therapeutic goal is to maintain cardiac function and minimize myocardial muscle damage. This is currently done either by the use of angioplasty or by fibrinolytic treatment of occluded vessels followed by drug therapy. Inotropic agents such as dopamine, dobutamine, isoproterenol, epinephrine and norepinephrine improve ventricular function and maintain cardiac output. These agents, however, increase oxygen requirements and long-term treatment may be harmful to a damaged heart and result in greater cardiac ischemia. Although the initial damage is caused by anoxia, the damage is exacerbated by the sudden reperfusion of oxygen into the heart leading to the generation of free radicals. As used in the specification and in the claims "ischemia/reperfusion injury" refers to the damage to cardiac muscle caused first by restriction of the blood supply followed by a sudden resupply of blood and the attendant generation of free radicals. Other bodily tissues are also subject to reperfusion injury when ischemia, a decrease in the blood supply to the tissue, is followed by reperfusion, a sudden perfusion of oxygen into the deprived tissue. There is a need, therefore, for a treatment for acute cardiac injury that would prevent ischemia and reperfusion injuries, that is damage that results from exposure of the cardiac muscle to reactive oxygen species.
There has been increasing recognition in recent years of the importance of diastolic relaxation during the normal pumping mechanism as well as systolic function, and that diastolic dysfunction can also lead to heart failure (Braunwald, (Harrison's Principles of Internal Medicine,13th ed., Isselbacher, et al.eds.,Ch. 194 and 195, 1994). Bonow et al.,("Left ventricular diastolic dysfunction as a cause of congestive heart failure", Annals of Internal Medicine, 117:502-510, 1992) report that up to 40% of patients presenting with congestive heart failure have preserved left ventricular function and suggest that diastolic dysfunction should be considered in patients with symptoms of heart failure who have normal systolic function. This information suggests that an agent that improved diastolic dysfunction, i.e., a lucinotropic agent, would be beneficial, as well as an agent that improved systolic function, i.e., an inotropic agent, in treating chronic or acute cardiac failure.
Pyruvate is a metabolically active compound common to metabolic pathways of glucose, lipid, and amino acids in animals.
In the heart it serves as an energy-yielding substrate. In preclinical studies it has been shown to increase metabolic rate, reduce weight and fat gain and improve insulin sensitivity in diabetic animals. It has also been demonstrated to be an effective antioxidant that reduces damage to heart tissue during ischemia and reperfusion injury.
Pyruvate is active when administered both enterally and parenterally. However, when administered enterally it must be in the form of a mineral salt. This has the negative side-effect of delivering excessive amounts of electrolytes such as sodium (Na.sup.+), calcium (Ca.sup.2+), or potassium (K.sup.+). The propyruvate, pyruvylglycine, was developed to avoid the excessive intake of pyruvate salts, which would result in, for example, sodium overload in cardiac patients.
Neither pyruvate nor pyruvylglycine is known to be acutely toxic. Both have been fed at high levels, 10% of the diet, for up to 28 days to laboratory animals with no noticeable toxic effects seen either on necropsy or pathological review.
Pyruvate has been tested for activity in treating obesity, diabetes and damage to kidney cells. Salahudeen et al. ("Hydrogen Peroxide-induced Renal Injury", Journal of Clinical Investigation, 88:1886-1893, 1991) found that pyruvate protects renal tissue in vitro and in vivo from injury caused by the strong oxidant, hydrogen peroxide (H.sub.2 O.sub.2). When the diet of pigs (Stanko et al , "Reduction of Carcass Fat in Swine With Dietary Addition of Dihydroxyacetone and Pyruvate", Journal of Animal Science, 67:1271-1278, 1989) or rats (Stanko et al., "Inhibition of Lipid Accumulation and Enhancement of Energy Expenditure by the Addition of Pyruvate and Dihydroxyacetone to a Rat Diet", Metabolism, 35:2,182-186,1986) was supplemented with pyruvate the rates of weight gain and fat deposition were reduced. Pyruvate supplementation of weight reduction diets for obese human subjects also resulted in increased weight and fat loss when compared to controls (Stanko et al., "Body composition, energy utilization, and nitrogen metabolism with a 4,25-Mj/d low-energy diet supplemented with pyruvate", American Journal of Clinical Nutrition, 56:630-635, 1992; Stanko et al., "Body composition, energy utilization, and nitrogen metabolism with a severely restricted diet supplemented with dihydroxyacetone and pyruvate", American Journal of Clinical Nutrition, 55:771-776, 1992). U.S. Pat. No. 5,047,4270 (Williamson, "Treatment for Secondary Diabetes Effects" discloses that pyruvate is effective in preventing vascular damage in diabetic rats.
Several patents teach the use of pyruvate in the management of obesity problems and improving insulin resistance and disclose methods of synthesizing modifications of pyruvate (pyruvate analogs), which may eliminate the problem of electrolyte overload which occurs when pyruvate is administered in the form of a pyruvate salt.
U.S. Pat. No. 4,548,937 (Stanko et al., "Method for Preventing Body Fat Deposition in Mammals") discloses a method for minimizing weight gain by adding pyruvate to the diet. U.S. Pat. No. 5,256,697 (Miller et al., "Method of Administering Pyruvate and Methods of Synthesizing Pyruvate Precursors") discloses a method of minimizing weight gain by administering pyruvate precursors orally in the diet. Pyruvate precursors, also known as pyruvate analogs, were synthesized in order to avoid the well-known problems ensuing from ingesting large amounts of salts which previously accompanied the ingestion of pyruvate. U.S. Pat. No. 5,312,985 (Dhaon et al., "Method of Synthesizing the Pyruvate Precursor Pyruvamide") was filed as a divisional of U.S. Pat. No. 5,256,697. Dhaon et al. claim a novel method of synthesizing a pyruvate analog, pyruvamide, which can be tested for efficacy in the management of various human metabolic diseases. Dhaon et al. also disclose a novel method of synthesis of various pyruvate analogs, particularly pyruvyl-amino acids, in which covalently linked amino acids replace the salts complexed to pyruvate. Pyruvylglycine was among the pyruvate analogs synthesized.
U.S. Pat. No. 5,283,260 (Miller et al., "Method for Reducing Insulin Resistance in Mammals") was also filed as a divisional of what is now U.S. Pat. No. 5,256,697. In U.S. Pat. No. 5,283,260 Miller et al. claim a method of reducing insulin resistance by orally administering a pyruvyl-amino acid. Pyruvylglycine was shown to be effective in reducing insulin resistance when added to the diet of obese and diabetes-prone rats and, thus, useful in the management of Type II diabetes.
The two patents to Miller et al. and the patent to Dhaon et al. disclose the efficacy of pyruvate analogs, particularly pyruvylglycine, in the management of obesity related problems and excessive food intake. They also disclose a superior synthesis of some pyruvate analogs. However, they do not disclose the use of pyruvylglycine in treating heart disease, and, as will be shown below, the efficacy of pyruvylglycine in any particular application is presently neither predictable nor obvious. It is only possible to determine experimentally whether a particular pyruvate analog will be safe and efficacious in the management of a given medical condition.
There is also a substantial body of basic research into the effect of pyruvate on heart . Bunger et al. ("Pyruvate-enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart" European Journal of Biochemistry, 180:221-233, 1989) demonstrated the cardioprotective effect of pyruvate on guinea pig hearts during hypoxia, ischemia and reperfusion. Cavallini et al.,("The Protective Action of Pyruvate on Recovery of Ischemic Rat Heart: Comparison with Other Oxidizable Substrates" Journal of Molecular and Cellular Cardiology, 22:143-154, 1990) reported the protective action of pyruvate on ischemic rat hearts. The data of Mentzer et al. ("Effect of Pyruvate on Regional Ventricular Function in Normal and Stunned Myocardium", Annals of Surgery, 209:629-634, 1989) indicate that pyruvate enhances ventricular function in post-ischemic dog hearts. Pyruvate improved cardiac function in reperfused post-ischemic canine hearts (Mallet et al., "Pyruvate Enhanced Regional Function and Energetics in Post-Ischemic Canine Myocardium", Federation of American Societies for Experimental Biology Journal, A326:No.1890, 1993) and in rat hearts (DeBoer et al, "Pyruvate enhances recovery of rat hearts after ischemia and reperfusion by preventing free radical generation", American Journal of Physiology, 265:H1571-H1576, 1993) and de Groot et al., "The effects of exogenous lactate and pyruvate on the recovery of coronary flow in the rat heart after ischaemia", Cardiovascular Research, 27:1088-1093,1993) Zhou et al. reported at the 66th Meeting of the American Heart Association, ("Effects of Adenosine and Pyruvate on Regional Function and Myocardial Phosphorylation Potential in in vivo Stunned Porcine Myocardium", I-187 No 0997 1993) that treatment with pyruvate, 60 minutes after arterial occlusion of porcine hearts, during the last 30 minutes of reperfusion attenuated myocardial stunning.
U.S. Pat. No. 5,294,641 (Stanko, "Method for Treating a Medical Patient for Cardiac Trauma") teaches the use of pyruvate in the treatment of myocardial infarction and ischemia in order to reduce the oxygen demand of the heart.
Due to the importance of the problem of reperfusion injury, many compounds have been tested for efficacy. WO 92/08453 (Davies et al., "Hydroxamic Acids for Preventing Reperfusion Injury") discloses that various hydroxamic acid derivatives act as antioxidants in an in vitro system. Davies et al. teach the use of hydroxamic acids in the prevention and treatment of reperfusion injury.
The preceding references demonstrate that pyruvate is a cardioprotective substrate after hypoxic or ischemic damage to the heart such as occurs during coronary surgery. However, in order to administer effective doses of pyruvate under clinical conditions the required blood concentration of pyruvate would result in the patient receiving excessively high levels of electrolytes. There is, therefore, a need for an improved method of delivering pyruvate to patients with cardiovascular disease which would not require harmful levels of mineral salts and would confer the cardioprotective benefits of pyruvate.